Aqueous or pulverulent, water-dispersible preparation of a sparingly water-soluble pharmaceutical active compound and its preparation

ABSTRACT

An aqueous or pulverulent, water-dispersible pharmaceutical preparation which contains an emulsifier, a protective colloid and, in microdisperse form, an edible oil or fat, a sparingly water-soluble active compound being dissolved in the oil or fat, and a process for its preparation.

This application is a division of application Ser. No. 143,074, filed onJan. 12, 1988, now U.S. Pat. No. 4,935,245.

The present invention relates to the conversion of hydrophobic, i.e.water-insoluble or sparingly soluble, pharmaceutical active compoundsinto an aqueous liquid or pulverulent form, the active compound beingdissolved in an edible oil or fat, and the oil or fat solution being inthe form of very small droplets.

The pharmaceutical formulation of water-insoluble or sparingly solublepharmaceutical active compounds is always problematic if the activecompounds are to be used in water-compatible formulations. To ensurerapid bioavailability of such active compounds, very fine distributionof these compounds is desirable.

Various methods have been described for increasing the absorbability,all of which aim at reducing the size of the crystallites of the activecompounds. Most widely used are various milling processes, by means ofwhich the coarsely crystalline synthetic material can be converted to aparticle size range of, at best, from 2 to 10 μm. Although thisconstitutes an improvement over the initial situation, it is stillinsufficient in the case of sparingly soluble substances and completelyunsatisfactory in the case of virtually insoluble substances, such asthe carotenoids. A process described in U.S. Pat. No. 4,522,743constitutes a certain degree of progress in comparison. Although thisprocess gives an extremely fine distribution of the active compounds,the particle sizes being less than 1 μm, it still does not provide amolecular disperse distribution. Instead, solid particles are stilldetectable under the electron microscope.

Molecular disperse distributions in the form of solid solutions wereobtained by a very different method in which the active compounds wereconverted via a melt of a suitable matrix material, such as polyethyleneglycols or urea, into a molecular disperse state, from which a solidsolution was obtained after cooling, or the active compound, togetherwith a suitable polymer material, such as polyvinylpyrrolidone, wasdissolved in a chlorohydrocarbon, the solution was then spray dried andthe active compound was thus converted to a molecular disperse solidsolution (R. Voigt, Lehrbuch der pharmazeutischen Technologie, VerlagChemie, Weinheim, 5th Edition, 1984, page 472 et seq.).

However, the last-mentioned processes have considerable disadvantages.In the case of the melt process, heating during the process leads, interalia, to thermolytic losses of thermally unstable active compounds.Another serious disadvantage of such formulations is that, after thesolidified melt has been redissolved in an aqueous system, the activecompound frequently recrystallizes, so that the micronization effectinitially achieved is eliminated again before biological absorptiontakes place. It is also observed that recrystallization occurs even inthe solidified melt as a result of diffusion of the active compoundmolecules in the matrix, and the products have only a short shelf life.

The same disadvantages, i.e. recrystallization after redissolution inwater and poor shelf life, are also observed in the case of the productsobtained by the solution process. This process has the furtherconsiderable disadvantage that chlorohydrocarbons have to be used(chloroform, methylene chloride, etc.) in order to meet the requirementfor high solubility of both the hydrophobic active compound and thehydrophilic matrix material. Complete removal of the chlorohydrocarbons,which is necessary for toxicological reasons, is technically difficultto achieve.

The biological absorption of active compounds which are sparinglysoluble in aqueous media is influenced not only by their fineness butalso be endogenous and exogenous effects of the gastrointestinal tract.The endogenous factors (gastrointestinal secretion, peristaltics, pH,biotransformation) are biologically controlled in the absence ofpathological changes in the gastrointestinal tract and are thuspredetermined and not very variable. On the other hand, exogenousfactors which are influenced by the dietary habits of the patient mayvary considerably. In the case of sparingly water-soluble, lipophilicactive compounds, the fat content of the food consumed together with thedrug has an important effect on absorption behavior.

It is an object of the present invention to provide aqueous orpulverulent pharmaceutical preparations which do not have the stateddisadvantages but contain the sparingly water-soluble or virtuallyinsoluble active compound in molecular disperse form, and from which,when pulverulent preparations are dissolved in aqueous systems(gastrointestinal tract, infusion solutions), the active compound isliberated in molecular disperse form, so that differences in the fatcontent of the food consumed together with the drug are unimportant.

We have found that this object is achieved, according to the invention,if the active compound, together with from 2 to 20 times the weight ofan edible fat or preferably, oil and an emulsifier is dissolved in avolatile, water-miscible, organic solvent at from 10° to 240° C.,preferably from 100° to 200° C., under atmospheric or superatmosphericpressure, the solvent is transferred to the aqueous phase from theresulting molecular disperse solution by mixing with an aqueous solutionof a protective colloid at from 0° to 50° C., the oil or fat whichcontains the active compound in solution forming a microdisperse phase,and the resulting two-phase mixture is freed from the solvent and, whererelevant, the water in a conventional manner.

A viscous liquid (oil-in-water emulsion) is obtained, from which thesolvent can be removed in a conventional manner, depending on theboiling point, for example by distillation, under atmospheric or reducedpressure, or by extraction with a water-immiscible solvent. Preferably,however, the solvent is removed together with the water by spray dryingor spray granulation.

The dry powder thus obtained can be redissolved in water to give auniform fine distribution of the oily active compound solution having aparticle size range of less than 1 μm.

If necessary, the microdisperse oil or fat phase laden with activecompound can also be brought to a suitable pH and then flocculatedtogether with the protective colloid and thus converted to a form fromwhich the solvent and a major part of the water can be separated in asimple manner by filtration or centrifuging. The coacervate thusobtained is then further dried in a conventional manner and converted togranules.

Active compounds which can be used for carrying out the invention have apositive value of the logarithmic n-octanol/water distributioncoefficient, log P (A. Leo and C. Hansch, Substituent Constants forCorrelation Analysis in Chemistry and Biology, Wiley, N.Y. 1979). Activecompounds having a log P value of greater than 1 are preferred.

Water-miscible, heat-stable, volatile solvents containing only carbon,hydrogen and oxygen are particularly suitable for carrying out the novelprocess, examples being alcohols, ethers, esters, ketones and acetals.Methanol, ethanol, n-propanol, isopropanol, butane-1,2-diol 1 methylether, propane-1,2-diol 1-n-propyl ether and acetone are preferablyused. In general, it is advantageous to use solvents which are not lessthan 10% water-miscible, have a boiling point of less than 200° C. andcontain less than 7 carbon atoms.

Suitable edible oils or fats are those which are liquid at 50° C.,preferably 30° C. Examples are vegetable oils, such as corn oil, oliveoil, poppy-seed oil, rape oil, castor oil, coconut oil, sesame oil,Aradisol soybean oil, peanut oil, sunflower oil, palm oil or cottonseedoil. Peanut oil is particularly preferred. Other suitable oils or fatsare the fish oils which are rich in eicosapentenoic acid anddocosahexenoic acid, as well as neat's foot oil, shortening, beefdripping and butter fat.

Examples of suitable emulsifiers are esters of long-chain fatty acidswith ascorbic acid, in particular ascorbyl palmitate, mono- anddiglycerides of fatty acids and their oxyethylation products, esters ofmono-fatty acid glycerides with acetic acid, citric acid, lactic acid ordiacetyltartaric acid, polyglycerol fatty esters (for example themonostearate of triglycerol), sorbitan fatty acid esters, propyleneglycol fatty acid esters, 2-(2'-stearoyllactyl)-lactic acid salts andlecithin.

Examples of protective colloids are polypeptides, such as gelatin,casein, caseinate, polysaccharides, such as starch, dextrin, dextran,pectin and gum arabic, as well as whole milk, skimmed milk, milk powderor mixtures of these. However, it is also possible to use polyvinylalcohol, vinyl polymers, for example polyvinylpyrrolidone, (meth)acrylicacid polymers and copolymers, methylcellulose, carboxymethylcellulose,hydroxypropylcellulose and alginates. For further details, reference maybe made to R. A. Morton, Fast Soluble Vitamins, Intern. Encyclopedia ofFood and Nutrition, Vol. 9, Pergamon Press 1970, pages 128-131.

To improve the technological properties of the end product, it isadvantageous to add to the colloid a plasticizer, such as sugars orsugar alcohols, eg. sucrose, glucose, lactose, invert sugar, sorbitol,mannitol or glycerol. Minor amounts of, for example, methylparaben,propylparaben, sorbic acid and/or Na benzoate may be added aspreservatives.

Other pharmaceutical auxiliaries, such as binders, disintegratingagents, flavor materials, vitamins, colorants, stabilizers, wettingagents and additives which influence the pH (cf. H. Sucker et al.,Pharmazeutische Technologie, Thieme-Verlag, Stuttgart 1978), can also beintroduced via the solvent or the aqueous phase. For example, in orderto increase the stability of the active compound to oxidativedegradation, it is often advantageous to use stabilizers, such asα-tocopherol, lecithin, tert-butylhydroxytoluene,tert-butylhydroxyanisole, ethoxyquins or ascorbyl palmitate. They can beadded to either the aqueous phase or the solvent phase but arepreferably dissolved together with the oil or fat in the solvent phase.

The pharmaceutical preparations obtainable according to the inventioncontain from 0.5 to 34, preferably from 2 to 20, % by weight of activecompound, from 2.5 to 68% by weight of an edible oil or fat, from 5 to50% by weight of a protective colloid, from 0.1 to 30, preferably from 1to 10, % by weight of one or more emulsifiers and from 0 to 70% byweight of a plasticizer, with or without minor amounts of stabilizersand with or without other pharmaceutical auxiliaries (up to a total of60% by weight), all percentages being based on the dry material; themean particle size of the solution of the active compound in the oil orfat in the form of the powder is less than 0.5 μm. The product containsvirtually no oil or fat particles having a particle size greater than 1μm.

Specifically, the novel process is carried out as follows, for exampleusing an apparatus as shown schematically in FIG. 1.

The apparatus is divided into parts I, II and III. Part II may be thehigh temperature section, while in parts I and III the temperatures areless than 50° C.

In vessel (1), a suspension of the active compound is initially takentogether with the oil or fat in the selected solvent, with or withoutthe addition of from 0.1 to 10% by weight, based on the mixture, ofstabilizers. If it is heat-sensitive and sparingly soluble at roomtemperature and therefore has to be dissolved rapidly at elevatedtemperatures, the active compound should be in finely milled form(particle size <50 μm). Vessel (2) contains the solvent without admixedactive compound. The suspension of active compound and the solvent arefed to mixing chamber (7) via the pumps (3) and (4) respectively; themixing ratio can be predetermined by selecting the particular deliveryof the pumps and is chosen so that, depending on the solubility of theactive compound in the solvent and the desired residence time, theresulting concentration of active compound in the mixing chamber is from0.5 to 10% by weight, based on the solution. In the case of aheat-sensitive active compound, the volume of the mixing chamber (7) ispreferably such that the residence time in (7) is preferably less than 1second at the selected delivery of the pumps (3) and (4).

Before entering the mixing chamber, the solvent is brought to thedesired temperature by means of the heat exchanger (6), while theoil-containing suspension of active compound is kept at below 50° C. byfeeding it via the thermally insulated line (5). As a result ofturbulent mixing in (7) at from 10° to 240° C., preferably from 100° to200° C. (in the case of active compounds and oils which are onlysparingly soluble at room temperature even in the most suitablesolvent), both the active compound and the oil or fat dissolve, and theresulting solution passes via the overflow (8), after a short residencetime, preferably less than 1 second in the case of heat-sensitivesubstances, into the second mixing chamber (11), in which admixing of anaqueous protective colloid/plasticizer solution via the pump (9) and thefeed line (10) results in division of the molecular disperse solution ofactive compound into a two-phase mixture with formation of amicrodisperse oil or fat phase containing the active compound insolution and a homogeneous, aqueous phase containing the water-misciblesolvent and the protective colloid. The microdisperse two-phase mixtureis then discharged via line (12) and the pressure relief valve, and fedto stock vessel (14). To obtain a very high concentration of activecompound, the emulsion can be circulated via the suction line (15).

If the pressure relief valve (13) is set at above 1 bar, it is evenpossible to use solvents at temperatures above their boiling point(under atmospheric pressure) in the novel process.

A pulverulent preparation can be obtained from the emulsion in aconventional manner, for example as described in DE-A 25 34 091, byspray drying or by spray cooling or by coating of the particles,isolation and drying in a fluidized bed.

For spray drying, the emulsion is either first freed from the solvent bydistillation, preferably under reduced pressure, or by extraction with awater-immiscible solvent, or the entire mixture is spray dried and waterand solvent stripped off together in the spray tower in this manner.

The pulverulent active compound is generally obtained in a dry orfree-flowing form at the bottom of the spray tower. In some cases, itmay be advantageous additionally to carry out complete drying in afluidized bed.

Instead of preparing the powder formulation by spray drying, it is alsopossible to use any other methods to convert the active compoundsalready finely distributed in the water/oil/solvent dispersion intopowder form. In a known method which is equally suitable for gel-formingprotective colloids and assistants, for example, the O/W emulsion freedfrom the solvent is emulsified with liquid paraffin to give an O/W/Odouble emulsion, the mixture is cooled, the liquid paraffin is separatedfrom the gelled particles, and the resulting preparation is washed withnaphtha and dried in a fluidized bed.

In the novel procedure, it is particularly surprising that the use ofthe stated water-miscible solvents mixed with an edible oil or fat andemulsifiers permits the preparation of supersaturated solutions fromwhich, in the microdisperse oil phase after the phase separation inducedby the turbulent mixing with the aqueous protective colloid solution,even during removal of the volatile solvent, for example by spraydrying, and after cooling, no recrystallization of the active compoundoccurs within the submicroscopic oil droplets laden (theoreticallyoverladen) with the active compound.

It is also surprising that mixing the solvent-containing oil solution ofthe active compounds with the aqueous protective colloid solutioninduces a phase separation in which the disperse oil phase is obtainedin the form of extremely small particles, as are scarcely obtainable bymechanical homogenization. This finely divided state of the oil phaseladen with active compound is surprisingly retained even during removalof the volatile solvent, for example by spray drying. It is easilypossible to obtain preparations in which the major part of the oil phasehas a particle size of 0.2 μm without oil particles greater than 1 μmsimultaneously being present.

By an appropriate choice of the protective colloid, it is possible toprepare powder preparations whose dissolution properties in aqueousmedia can be adjusted as desired from rapid solubility in cold water topoor solubility, the oil phase in each case being in the form ofsubmicroscopic, readily absorbable particles. It is even possible toobtain preparations which liberate the microdisperse oil phase onlyafter enzymatic degradation of the protective colloid and under pHcontrol along the intestinal tract.

The Examples which follow illustrate the novel process.

EXAMPLE 1

18 g of 1,7-bis-(3-methoxyphenyl)-3-methylaza-7-cyanononadecanehydrochloride monohydrate (anipamil hydrochloride) were suspended withvigorous stirring, in a solution of 14.5 g of ascorbyl palmitate,together with 73 g of peanut oil in 1 l of isopropanol, the pressurerelief valve (13) was set at 25 bar and the said suspension was mixed inthe mixing chamber (7) with isopropanol which had been heated to 225° C.in the heat exchanger (6). With the suspension being metered at 2 l/hand the solvent at 3 l/h, the residence time in the mixing chamber (7)was 0.35 second. The molecular disperse solution formed at 190° C. wasthen fed to the mixing chamber (11), in which turbulent mixing with anaqueous solution of 15 g of gelatine and 22.5 g of sucrose per liter,brought to pH 9 with 1N NaOH, at a metering rate of 27 l/h, resulted inphase separation with formation of a microdisperse oil phase whichcontained the anipamil in solution. In the collecting vessel (14), amicrodisperse two-phase mixture at 50° C. was obtained. Particle sizeanalysis by proton correlation spectroscopy (according to B. Chu, LaserLight Scattering, Academic Press, New York 1974) gave a value of 240 nmfor the mean particle diameter of the oil phase and a distribution widthof ±40%.

Removal of the solvent under reduced pressure at 50° C. in adistillation apparatus gave a viscous liquid which could be converted toa stable, water-soluble dry powder by spray drying. The anipamil contentof this dry powder was 2.4% by weight.

Redissolving the dry powder in cold water gave a solution in which theoil phase was again in the form of a microdisperse phase, the particlesize being 310 nm ±40%.

EXAMPLE 2

10 g of1-(3-methyl-4-nitroimidazol-2-yl)-2-(5-ethyl-1,3,4-thiadiazol-2-yl)-prop-1-enewere suspended in a solution of 8 g of ascorbyl palmitate together with40 g of peanut oil in 192 g of isopropanol, and micronized in the samemanner as in Example 1. The particle size distribution of the oil phaseladen with active compound in the micronized material corresponded tothat of the micronized material of Example 1.

EXAMPLE 3

5 g of 2'-(2-hydroxy-3-propylaminopropoxy)-3-phenylpropiophenone(propafenone) were suspended in 240 g of a solution of 4 g of the esterof diacetyltartaric acid with mono-fatty acid glyceride together with 20g of peanut oil in isopropanol and micronized in the same manner as inExample 1. In the micronized material, the mean particle size of the oilphase laden with active compound was 184 nm ±29%.

EXAMPLES 4-19

Micronized materials having the same physicochemical properties as themicronized material from Example 1 were prepared in the same manner asin Example 1, using the active compounds listed in the Table below.

    __________________________________________________________________________                                Mean particle                                                                 size of the oil                                                               phase laden with                                                              active compound,                                  Example                                                                             Active compound       in nm                                             __________________________________________________________________________     4    (Z)-2-chloro-10-(4-methylpiperazinyl)-                                                              273 ± 44%                                            5H-dibenzo[a,d]cyclohepten-5-ylidene-                                         acetonitrile (Rilapin)                                                   5    11-(4-methylpiperazinylcarbonyl-                                                                    339 ± 33%                                            methylidene)-5,11-dihydro-6H-dibenz[b,e]-                                     azepin-6-one                                                             6    1-(3-methyl-4-nitroimidazol-2-yl)-2-(5-                                                             362 ± 45%                                            ethyl-1,3,4-thiadiazol-2-yl)-prop-1-ene                                  7    Z-1-(1,2,4-triazol-1-yl-methyl)-1-(4-                                                               307 ± 36%                                            chlorophenyl)-2-(2,4-dichlorophenyl)-                                         oxirane                                                                  8    1-[3-(5-methyl-1,3,4-oxadiazol-2-yl)-                                                               286 ± 40%                                            phenoxy]-3-[4-(2-methoxyphenyl)-piperazin-                                    1-yl]-propan-2-ol fumarate (Nesapidil)                                   9    3-aza-7-cyano-1,7-bis(3,4-dimethoxyphenyl)-                                                         300 ± 37%                                            3,8-dimethylnonane (Verapamil)                                          10    3-methylaza-7-cyano-1,7-diphenylnonadecane                                                          240 ± 40%                                            (Ronipamil)                                                             11    1-bicyclo[2.2.1]hept-5-en-2-yl-1-phenyl-                                                            260 ± 35%                                            3-piperidinylpropan-1-ol (Biperiden)                                    12    2'-(2-hydroxy-3-n-propylaminopropoxy)-                                                              269 ± 38%                                            3-phenylpropiophenone (Propafenone)                                     13    5,6-dihydro-4-methoxy-6-(2-phenylethenyl)-                                                          323 ± 34%                                            2H-pyran-2-one (Kawain)                                                 14    2-(4-i-butylphenyl)propionic acid                                                                   265 ± 37%                                            (Ibuprofen)                                                             15    4-(2-piperidinylhydroxymethyl)-2,8-bis-                                                             335 ± 42%                                            trifluoromethylquinoline (Mefloquine)                                   16    7-chloro-1,3-dihydro-1-methyl-5-phenyl-                                                             303 ± 45%                                            2-H-1,4-benzodiazepin-2-one (Diazepam)                                  17    5-amidocarbonyl-5H-dibenz[b,f]azepine                                                               313 ± 41%                                            (Carbamazepine)                                                         18    1,3-bis(2-carboxy-4-oxochromen-5-yl-                                                                313 ± 40%                                            oxy)-1,3-propan-2-ol, disodium salt                                           (sodium chromoglycate)                                                  19    3-amino-N-(2-dimethylaminoethyl)-1,8-                                                               286 ±  30%                                           naphthalimide (Amonafide)                                               __________________________________________________________________________

We claim:
 1. An aqueous pharmaceutical composition which consistsessentially of an emulsifier, a protective colloid and, in the form ofparticles of less than 1 micron in diameter, an edible oil or fat, asparingly water-soluble active compound being dispersed in the oil orfat, wherein the weight ratio of edible oil or fat to active compound is2 to 20:1.
 2. An aqueous pharmaceutical preparation as defined in claim1, wherein the active compound has a positive logarithmic octanol/waterdistribution coefficient.
 3. An aqueous pharmaceutical preparation asdefined in claim 2, wherein the logarithmic octanol/water distributioncoefficient of the active compound is >1.
 4. An aqueous pharmaceuticalpreparation as defined in claim 1, wherein the mean diameter of the oilor fat particles is less than 0.5 μm.
 5. An aqueous pharmaceuticalpreparation as defined in claim 1, which contains the followingcomponents in the following amounts, based on the dry material:from 0.5to 34% by weight of active compound, from 2.5 to 68% by weight of anedible oil or fat, from 5 to 50% by weight of a protective colloid, from0.1 to 30% by weight of an emulsifier, from 0 to 70% by weight of aplasticizer and from 0 to 60% by weight of one or more pharmaceuticalauxiliaries.